Millions of postmenopausal women with an intact uterus are prescribed combined hormone replacement therapy (HRT), consisting of both estrogens and progestins, to diminish menopausal symptoms; progestins negate the proliferative effects of estrogens in the uterus, which can lead to endometrial cancer. Unfortunately, studies show that combined HRT increases the risk of breast cancer, compared to women who receive estrogens alone. Thus there is a need to design strategies that will negate the proliferative effects of progestins in breast. There is growing evidence that the Indian spice, curcumin, and the estrogen metabolite 2-methoxyestradiol (2-ME2), function as anti-angiogenic and anti-cancer compounds in numerous types of cancer. However, the effects of curcumin and 2-ME2 on progestin-driven breast cancer have not been studied. The purpose of this study is to explore the effectiveness of curcumin and 2-ME2 as angiogenic inhibitors of progestin-dependent breast cancer. It is hypothesize that curcumin and 2-ME2 will inhibit progestin-dependent breast cancer by inhibition the potent angiogenic protein vascular endothelial growth factor (VEGF). To prove this hypothesis, three specific aims will be addressed: (1) Determine whether curcumin and 2-ME2 will inhibit progestin-induced VEGF secretion from human breast cancer cells. Cell culture analysis will be conducted to investigate this aim; (2) elucidate the mechanism by which 2-ME2 and curcumin inhibit progestin-dependent VEGF induction. Investigatory procedures include immunoblotting, luciferase reporter assays, and DNA-binding analysis; and (3) determine the effectiveness of curcumin and 2-ME2 as treatments and preventative agents in vivo in progestin-accelerated breast cancer xenograft model in nude mice in DMBA-induced mammary cancer model. This study will investigate the possibility that curcumin and 2-ME2 can inhibit the growth of new blood vessels in progestin-dependent breast tumors. Positive outcomes from these experiments would suggest that curcumin and/or 2-ME2 could be considered as chemopreventive or therapeutic agents for progestin- dependent tumors in postmenopausal women undergoing combined hormone replacement therapy. [unreadable] [unreadable] [unreadable]